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Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept
Hae Young Chung, Dae Hyun Kim, Eun Kyeong Lee, Ki Wung Chung, Sangwoon Chung, Bonggi Lee, Arnold Y. Seo, Jae Heun Chung, Young Suk Jung, Eunok Im, Jaewon Lee, Nam Deuk Kim, Yeon Ja Choi, Dong Soon Im, Byung Pal Yu
Aging and disease    2019, 10 (2): 367-382.   DOI: 10.14336/AD.2018.0324
Abstract960)   HTML1)    PDF(pc) (607KB)(1188)       Save

Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required. In this review, we discuss newly emerging data on multi-phase inflammatory networks and proinflammatory pathways as they relate to aging. We describe the age-related upregulation of nuclear factor (NF)-κB signaling, cytokines/chemokines, endoplasmic reticulum (ER) stress, inflammasome, and lipid accumulation. The later sections of this review present our expanded view of age-related senescent inflammation, a process we term “senoinflammation”, that we propose here as a novel concept. As described in the discussion, senoinflammation provides a schema highlighting the important and ever-increasing roles of proinflammatory senescence-associated secretome, inflammasome, ER stress, TLRs, and microRNAs, which support the senoinflammation concept. It is hoped that this new concept of senoinflammation opens wider and deeper avenues for basic inflammation research and provides new insights into the anti-inflammatory therapeutic strategies targeting the multiple proinflammatory pathways and mediators and mediators that underlie the pathophysiological aging process.

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BDNF Alleviates Neuroinflammation in the Hippocampus of Type 1 Diabetic Mice via Blocking the Aberrant HMGB1/RAGE/NF-κB Pathway
Rongrong Han, Zeyue Liu, Nannan Sun, Shu Liu, Lanlan Li, Yan Shen, Jianbo Xiu, Qi Xu
Aging and disease    2019, 10 (3): 611-625.   DOI: 10.14336/AD.2018.0707
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Diabetes is a systemic disease that can cause brain damage such as synaptic impairments in the hippocampus, which is partly because of neuroinflammation induced by hyperglycemia. Brain-derived neurotrophic factor (BDNF) is essential in modulating neuroplasticity. Its role in anti-inflammation in diabetes is largely unknown. In the present study, we investigated the effects of BDNF overexpression on reducing neuroinflammation and the underlying mechanism in mice with type 1 diabetes induced by streptozotocin (STZ). Animals were stereotactically microinjected in the hippocampus with recombinant adeno-associated virus (AAV) expressing BDNF or EGFP. After virus infection, four groups of mice, the EGFP+STZ, BDNF+STZ, EGFP Control and BDNF Control groups, received STZ or vehicle treatment as indicated. Three weeks later brain tissues were collected. We found that BDNF overexpression in the hippocampus significantly rescued STZ-induced decreases in mRNA and protein expression of two synaptic plasticity markers, spinophilin and synaptophysin. More interestingly, BDNF inhibited hyperglycemia-induced microglial activation and reduced elevated levels of inflammatory factors (TNF-α, IL-6). BDNF blocked the increase in HMGB1 levels and specifically, in levels of one of the HMGB1 receptors, RAGE. Downstream of HMGB1/RAGE, the increase in the protein level of phosphorylated NF-κB was also reversed by BDNF in STZ-treated mice. These results show that BDNF overexpression reduces neuroinflammation in the hippocampus of type 1 diabetic mice and suggest that the HMGB1/RAGE/NF-κB signaling pathway may contribute to alleviation of neuroinflammation by BDNF in diabetic mice.

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Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade
Navneet Kumar Dubey, Hong-Jian Wei, Sung-Hsun Yu, David F. Williams, Joseph R. Wang, Yue-Hua Deng, Feng-Chou Tsai, Peter D. Wang, Win-Ping Deng
Aging and disease    2019, 10 (3): 483-496.   DOI: 10.14336/AD.2018.0616
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Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

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The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases
Huachen Huang, Shanshan Song, Suneel Banerjee, Tong Jiang, Jinwei Zhang, Kristopher T. Kahle, Dandan Sun, Zhongling Zhang
Aging and disease    2019, 10 (3): 626-636.   DOI: 10.14336/AD.2018.0928
Accepted: 02 October 2018

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In recent years, cation-chloride cotransporters (CCCs) have drawn attention in the medical neuroscience research. CCCs include the family of Na+-coupled Cl- importers (NCC, NKCC1, and NKCC2), K+-coupled Cl- exporters (KCCs), and possibly polyamine transporters (CCC9) and CCC interacting protein (CIP1). For decades, CCCs have been the targets of several commonly used diuretic drugs, including hydrochlorothiazide, furosemide, and bumetanide. Genetic mutations of NCC and NKCC2 cause congenital renal tubular disorders and lead to renal salt-losing hypotension, secondary hyperreninemia, and hypokalemic metabolic alkalosis. New studies reveal that CCCs along with their regulatory WNK (Kinase with no lysine (K)), and SPAK (Ste20-related proline-alanine-rich kinase)/OSR1(oxidative stress-responsive kinase-1) are essential for regulating cell volume and maintaining ionic homeostasis in the nervous system, especially roles of the WNK-SPAK-NKCC1 signaling pathway in ischemic brain injury and hypersecretion of cerebrospinal fluid in post-hemorrhagic hydrocephalus. In addition, disruption of Cl- exporter KCC2 has an effect on synaptic inhibition, which may be involved in developing pain, epilepsy, and possibly some neuropsychiatric disorders. Interference with KCC3 leads to peripheral nervous system neuropathy as well as axon and nerve fiber swelling and psychosis. The WNK-SPAK/OSR1-CCCs complex emerges as therapeutic targets for multiple neurological diseases. This review will highlight these new findings.

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Processing of Mutant β-Amyloid Precursor Protein and the Clinicopathological Features of Familial Alzheimer’s Disease
Christopher Bi, Stephanie Bi, Bin Li
Aging and disease    2019, 10 (2): 383-403.   DOI: 10.14336/AD.2018.0425
Accepted: 12 November 2018

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Alzheimer’s disease (AD) is a complex, multifactorial disease involving many pathological mechanisms. Nonetheless, single pathogenic mutations in amyloid precursor protein (APP) or presenilin 1 or 2 can cause AD with almost all of the clinical and neuropathological features, and therefore, we believe an important mechanism of pathogenesis in AD could be revealed from examining pathogenic APP missense mutations. A comprehensive review of the literature, including clinical, neuropathological, cellular and animal model data, was conducted through PubMed and the databases of Alzforum mutations, HGMD, UniProt, and AD&FTDMDB. Pearson correlation analysis combining the clinical and neuropathological data and aspects of mutant APP processing in cellular models was performed. We find that an increase in Aβ42 has a significant positive correlation with the appearance of neurofibrillary tangles (NFTs) and tends to cause an earlier age of AD onset, while an increase in Aβ40 significantly increases the age at death. The increase in the α-carboxyl terminal fragment (CTF) has a significantly negative correlation with the age of AD onset, and β-CTF has a similar effect without statistical significance. Animal models show that intracellular Aβ is critical for memory defects. Based on these results and the fact that amyloid plaque burden correlates much less well with cognitive impairment than do NFT counts, we propose a “snowball hypothesis”: the accumulation of intraneuronal NFTs caused by extracellular Aβ42 and the increase in intraneuronal APP proteolytic products (CTFs and Aβs) could cause cellular organelle stress that leads to neurodegeneration in AD, which then resembles the formation of abnormal protein “snowballs” both inside and outside of neurons.

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The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases
Wenjun Tu, Hong Wang, Song Li, Qiang Liu, Hong Sha
Aging and disease    2019, 10 (3): 637-651.   DOI: 10.14336/AD.2018.0513
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Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites or [reactive oxygen species (ROS)] and their elimination by through protective mechanisms, including (antioxidants). This Such imbalance leads to damage of cells and important biomolecules and cells, with hence posing a potential adverse impact on the whole organism. At the center of the day-to-day biological response to oxidative stress is the Kelch-like ECH-associated protein 1 (Keap1) - nuclear factor erythroid 2-related factor 2 (Nrf2)- antioxidant response elements (ARE) pathway, which regulates the transcription of many several antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in the maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and pro-apoptotic conditions, which allows us to consider it as a pharmacological target. Herein, we review and discuss the recent advancements in the regulation of the Keap1/Nrf2/ARE system, and its role under physiological and pathophysiological conditions, e.g. such as in exercise, diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, stroke, liver and kidney system, etc. and such.

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The Potential Markers of Circulating microRNAs and long non-coding RNAs in Alzheimer's Disease
Yanfang Zhao, Yuan Zhang, Lei Zhang, Yanhan Dong, Hongfang Ji, Liang Shen
Aging and disease    2019, 10 (6): 1293-1301.   DOI: 10.14336/AD.2018.1105
Accepted: 13 November 2018

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Alzheimer’s disease (AD) is a neurodegenerative disorder and one of the leading causes of disability and mortality in the late life with no curative treatment currently. Thus, it is urgently to establish sensitive and non-invasive biomarkers for AD diagnosis, particularly in the early stage. Recently, emerging number of microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs) are considered as effective biomarkers in various diseases as they possess characteristics of stable, resistant to RNAase digestion and many extreme conditions in circulatory fluid. This review highlights recent advances in the identification of the aberrantly expressed miRNAs and lncRNAs in circulatory network for detection of AD. We summarized the abnormal expressed miRNAs in blood and cerebrospinal fluid (CSF), and detailed discussed the functions and molecular mechanism of serum or plasma miRNAs-miR-195, miR-155, miR-34a, miR-9, miR-206, miR-125b and miR-29 in the regulation of AD progression. In addition, we also elaborated the role of circulating lncRNA major including beta-site APP cleaving enzyme 1 (BACE1) and its antisense lncRNA BACE1-AS in AD pathological advancement. In brief, confirming the aberrantly expressed circulating miRNAs and lncRNAs will provide an effective testing tools for treatment of AD in the future.

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The role of CD2AP in the Pathogenesis of Alzheimer's Disease
Qing-Qing Tao, Yu-Chao Chen, Zhi-Ying Wu
Aging and disease    2019, 10 (4): 901-907.   DOI: 10.14336/AD.2018.1025
Accepted: 08 December 2018

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Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by irreversible decline in cognition with unclear pathogenesis. Recently, accumulating evidence has revealed that CD2 associated protein (CD2AP), a scaffolding molecule regulates signal transduction and cytoskeletal molecules, is implicated in AD pathogenesis. Several single nucleotide polymorphisms (SNPs) in CD2AP gene are associated with higher risk for AD and mRNA levels of CD2AP are decreased in peripheral lymphocytes of sporadic AD patients. Furthermore, CD2AP loss of function is linked to enhanced Aβ production, Tau-induced neurotoxicity, abnormal neurite structure modulation and reduced blood-brain barrier integrity. This review is to summarize the recent discoveries about the genetics and known functions of CD2AP. The recent evidence concerning the roles of CD2AP in the AD pathogenesis is summarized and CD2AP can be a promising therapeutic target for AD.

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Handgrip Strength and Pulmonary Disease in the Elderly: What is the Link?
Tatiana Rafaela Lemos Lima, Vívian Pinto Almeida, Arthur Sá Ferreira, Fernando Silva Guimarães, Agnaldo José Lopes
Aging and disease    2019, 10 (5): 1109-1129.   DOI: 10.14336/AD.2018.1226
Accepted: 31 December 2018

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Societies in developed countries are aging at an unprecedented rate. Considering that aging is the most significant risk factor for many chronic lung diseases (CLDs), understanding this process may facilitate the development of new interventionist approaches. Skeletal muscle dysfunction is a serious problem in older adults with CLDs, reducing their quality of life and survival. In this study, we reviewed the possible links between handgrip strength (HGS)—a simple, noninvasive, low-cost measure of muscle function—and CLDs in the elderly. Different mechanisms appear to be involved in this association, including systemic inflammation, chronic hypoxemia, physical inactivity, malnutrition, and corticosteroid use. Respiratory and peripheral myopathy, associated with muscle atrophy and a shift in muscle fiber type, also seem to be major etiological contributors to CLDs. Moreover, sarcopenic obesity, which occurs in older adults with CLDs, impairs common inflammatory pathways that can potentiate each other and further accelerate the functional decline of HGS. Our findings support the concept that the systemic effects of CLDs may be determined by HGS, and HGS is a relevant measurement that should be considered in the clinical assessment of the elderly with CLDs. These reasons make HGS a useful practical tool for indirectly evaluating functional status in the elderly. At present, early muscle reconditioning and optimal nutrition appear to be the most effective approaches to reduce the impact of CLDs and low muscle strength on the quality of life of these individuals. Nonetheless, larger in-depth studies are needed to evaluate the link between HGS and CLDs.

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Pyroptosis in Liver Disease: New Insights into Disease Mechanisms
Jiali Wu, Su Lin, Bo Wan, Bharat Velani, Yueyong Zhu
Aging and disease    2019, 10 (5): 1094-1108.   DOI: 10.14336/AD.2019.0116
Abstract105)   HTML1)    PDF(pc) (565KB)(949)       Save

There has been increasing interest in pyroptosis as a novel form of pro-inflammatory programmed cell death. The mechanism of pyroptosis is significantly different from other forms of cell death in its morphological and biochemical features. Pyroptosis is characterized by the activation of two different types of caspase enzymes—caspase-1 and caspase-4/5/11, and by the occurrence of a proinflammatory cytokine cascade and an immune response. Pyroptosis participates in the immune defense mechanisms against intracellular bacterial infections. On the other hand, excessive inflammasome activation can induce sterile inflammation and eventually cause some diseases, such as acute or chronic hepatitis and liver fibrosis. The mechanism and biological significance of this novel form of cell death in different liver diseases will be evaluated in this review. Specifically, we will focus on the role of pyroptosis in alcoholic and non-alcoholic fatty liver disease, as well as in liver failure. Finally, the therapeutic implications of pyroptosis in liver diseases will be discussed.

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Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity
Yaiza Potes, Zulema Pérez-Martinez, Juan C. Bermejo-Millo, Adrian Rubio-Gonzalez, María Fernandez-Fernández, Manuel Bermudez, Jose M. Arche, Juan J. Solano, Jose A. Boga, Mamen Oliván, Beatriz Caballero, Ignacio Vega-Naredo, Ana Coto-Montes
Aging and disease    2019, 10 (2): 217-230.   DOI: 10.14336/AD.2018.0430
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Aging is characterized by a progressive loss of skeletal muscle mass and function (sarcopenia). Obesity exacerbates age-related decline and lead to frailty. Skeletal muscle fat infiltration increases with aging and seems to be crucial for the progression of sarcopenia. Additionally, skeletal muscle plasticity modulates metabolic adaptation to different pathophysiological situations. Thus, cellular bioenergetics and mitochondrial profile were studied in the skeletal muscle of overweight aged people without reaching obesity to prevent this extreme situation. Overweight aged muscle lacked ATP production, as indicated by defects in the phosphagen system, glycolysis and especially mostly by oxidative phosphorylation metabolic pathway. Overweight subjects exhibited an inhibition of mitophagy that was linked to an increase in mitochondrial biogenesis that underlies the accumulation of dysfunctional mitochondria and encourages the onset of sarcopenia. As a strategy to maintain cellular homeostasis, overweight subjects experienced a metabolic switch from oxidative to lactic acid fermentation metabolism, which allows continued ATP production under mitochondrial dysfunction, but without reaching physiological aged basal levels. This ATP depletion induced early signs of impaired contractile function and a decline in skeletal muscle structural integrity, evidenced by lower levels of filamin C. Our findings reveal the main effector pathways at an early stage of obesity and highlight the importance of mitochondrial metabolism in overweight and obese individuals. Exploiting mitochondrial profiles for therapeutic purposes in humans is an ambitious strategy for treating muscle impairment diseases.

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The Role of Pathological Aging in Cardiac and Pulmonary Fibrosis
Lucy A. Murtha, Matthew Morten, Michael J. Schuliga, Nishani S. Mabotuwana, Sean A. Hardy, David W. Waters, Janette K. Burgess, Doan TM. Ngo, Aaron L. Sverdlov, Darryl A. Knight, Andrew J. Boyle
Aging and disease    2019, 10 (2): 419-428.   DOI: 10.14336/AD.2018.0601
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Aging promotes a range of degenerative pathologies characterized by progressive losses of tissue and/or cellular function. Fibrosis is the hardening, overgrowth and scarring of various tissues characterized by the accumulation of extracellular matrix components. Aging is an important predisposing factor common for fibrotic heart and respiratory disease. Age-related processes such as senescence, inflammaging, autophagy and mitochondrial dysfunction are interconnected biological processes that diminish the regenerative capacity of the aged heart and lung and have been shown to play a crucial role in cardiac fibrosis and idiopathic pulmonary fibrosis. This review focuses on these four processes of aging in relation to their role in fibrosis. It has long been established that the heart and lung are linked both functionally and anatomically when it comes to health and disease, with an ever-expanding aging population, the incidence of fibrotic disease and therefore the number of fibrosis-related deaths will continue to rise. There are currently no feasible therapies to treat the effects of chronic fibrosis therefore highlighting the importance of exploring the processes of aging and its role in inducing and exacerbating fibrosis of each organ. The focus of this review may help to highlight potential avenues of therapeutic exploration

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Necrostatin-1 Prevents Necroptosis in Brains after Ischemic Stroke via Inhibition of RIPK1-Mediated RIPK3/MLKL Signaling
Xu-Xu Deng, Shan-Shan Li, Feng-Yan Sun
Aging and disease    2019, 10 (4): 807-817.   DOI: 10.14336/AD.2018.0728
Accepted: 04 September 2018

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Pharmacological studies have indirectly shown that necroptosis participates in ischemic neuronal death. However, its mechanism has yet to be elucidated in the ischemic brain. TNFα-triggered RIPK1 kinase activation could initiate RIPK3/MLKL-mediated necroptosis under inhibition of caspase-8. In the present study, we performed middle cerebral artery occlusion (MCAO) to induce cerebral ischemia in rats and used immunoblotting and immunostaining combined with pharmacological analysis to study the mechanism of necroptosis in ischemic brains. In the ipsilateral hemisphere, we found that ischemia induced the increase of (i) RIPK1 phosphorylation at the Ser166 residue (p-RIPK1), representing active RIPK1 kinase and (ii) the number of cells that were double stained with P-RIPK1 (Ser166) (p-RIPK1+) and TUNEL, a label of DNA double-strand breaks, indicating cell death. Furthermore, ischemia induced activation of downstream signaling factors of RIPK1, RIPK3 and MLKL, as well as the formation of mature interleukin-1β (IL-1β). Treatment with necrostatin-1 (Nec-1), an inhibitor of necroptosis, significantly decreased ischemia-induced increase of p-RIPK1 expression and p-RIPK1+ neurons, which showed protection from brain damage. Meanwhile, Nec-1 reduced RIPK3, MLKL and p-MLKL expression levels and mature IL-1β formation in Nec-1 treated ischemic brains. Our results clearly demonstrated that phosphorylation of RIPK1 at the Ser166 residue was involved in the pathogenesis of necroptosis in the brains after ischemic injury. Nec-1 treatment protected brains against ischemic necroptosis by reducing the activation of RIPK1 and inhibiting its downstream signaling pathways. These results provide direct in vivo evidence that phosphorylated RIPK1 (Ser 166) plays an important role in the initiation of RIPK3/MLKL-dependent necroptosis in the pathogenesis of ischemic stroke in the rodent brain.

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Maintained Properties of Aged Dental Pulp Stem Cells for Superior Periodontal Tissue Regeneration
Linsha Ma, Jingchao Hu, Yu Cao, Yilin Xie, Hua Wang, Zhipeng Fan, Chunmei Zhang, Jinsong Wang, Chu-Tse Wu, Songlin Wang
Aging and disease    2019, 10 (4): 793-806.   DOI: 10.14336/AD.2018.0729
Accepted: 12 September 2018

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Owing to excellent therapeutic potential, mesenchymal stem cells (MSCs) are gaining increasing popularity with researchers worldwide for applications in tissue engineering, and in treatment of inflammation-related and age-related disorders. However, the senescence of MSCs over passaging has limited their clinical application owing to adverse effect on physiological function maintenance of tissues as well as disease treatment. An inflammatory microenvironment is one of the key contributors to MSC senescence, resulting in low regeneration efficiency. Therefore, MSCs with high resistance to cellular senescence would be a benefit for tissue regeneration. Toward this end, we analyzed the senescence properties of different types of stem cells during culture and under inflammation, including dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), bone marrow mesenchymal stem cells (BMMSCs), and adipose-derived stem cells (ADSCs). Overall, the DPSCs had higher proliferation rates, lower cellular senescence, and enhanced osteogenesis maintenance compared to those of non-dental MSCs cultured from passage three to six. The expression profiles of genes related to apoptosis, cell cycle, and cellular protein metabolic process (contributing to the cell self-renewal ability and metabolic processes) significantly differed between DPSCs and BMMSCs at passage three. Moreover, DPSCs were superior to BMMSCs with regards to resistance to lipopolysaccharide-induced apoptosis and senescence, with enhanced osteogenesis in vitro, and showed improved periodontal regeneration after injection in a miniature pig periodontitis model in vivo. Overall, the present study indicates that DPSCs show superior resistance to subculture and inflammation-induced senescence and would be suitable stem cells for tissue engineering with inflammation.

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Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways
Georg Fuellen, Ludger Jansen, Alan A Cohen, Walter Luyten, Manfred Gogol, Andreas Simm, Nadine Saul, Francesca Cirulli, Alessandra Berry, Peter Antal, Rüdiger Köhling, Brecht Wouters, Steffen Möller
Aging and disease    2019, 10 (4): 883-900.   DOI: 10.14336/AD.2018.1030
Accepted: 19 November 2018

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Despite increasing research efforts, there is a lack of consensus on defining aging or health. To understand the underlying processes, and to foster the development of targeted interventions towards increasing one’s health, there is an urgent need to find a broadly acceptable and useful definition of health, based on a list of (molecular) features; to operationalize features of health so that it can be measured; to identify predictive biomarkers and (molecular) pathways of health; and to suggest interventions, such as nutrition and exercise, targeted at putative causal pathways and processes. Based on a survey of the literature, we propose to define health as a state of an individual characterized by the core features of physiological, cognitive, physical and reproductive function, and a lack of disease. We further define aging as the aggregate of all processes in an individual that reduce its wellbeing, that is, its health or survival or both. We define biomarkers of health by their attribute of predicting future health better than chronological age. We define healthspan pathways as molecular features of health that relate to each other by belonging to the same molecular pathway. Our conceptual framework may integrate diverse operationalizations of health and guide precision prevention efforts.

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Interplay between Exosomes and Autophagy in Cardiovascular Diseases: Novel Promising Target for Diagnostic and Therapeutic Application
Jinfan Tian, Sharif Popal Mohammad, Yingke Zhao, Yanfei Liu, Keji Chen, Yue Liu
Aging and disease    2019, 10 (6): 1302-1310.   DOI: 10.14336/AD.2018.1020
Accepted: 20 November 2018

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Exosome, is identified as a nature nanocarrier and intercellular messenger that regulates cell to cell communication. Autophagy is critical in maintenance of protein homeostasis by degradation of damaged proteins and organelles. Autophagy and exosomes take pivotal roles in cellular homeostasis and cardiovascular disease. Currently, the coordinated mechanisms for exosomes and autophagy in the maintenance of cellular fitness are now garnering much attention. In the present review, we discussed the interplay of exosomes and autophagy in the context of physiology and pathology of the heart, which might provide novel insights for diagnostic and therapeutic application of cardiovascular diseases.

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MicroRNAs and the Genetic Nexus of Brain Aging, Neuroinflammation, Neurodegeneration, and Brain Trauma
Saumyendra N. Sarkar, Ashley E. Russell, Elizabeth B. Engler-Chiurazzi, Keyana N. Porter, James W. Simpkins
Aging and disease    2019, 10 (2): 329-352.   DOI: 10.14336/AD.2018.0409
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Aging is a complex and integrated gradual deterioration of cellular activities in specific organs of the body, which is associated with increased mortality. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, neurovascular disorders, and neurodegenerative diseases. There are nine tentative hallmarks of aging. In addition, several of these hallmarks are increasingly being associated with acute brain injury conditions. In this review, we consider the genes and their functional pathways involved in brain aging as a means of developing new strategies for therapies targeted to the neuropathological processes themselves, but also as targets for many age-related brain diseases. A single microRNA (miR), which is a short, non-coding RNA species, has the potential for targeting many genes simultaneously and, like practically all other cellular processes, genes associated with many features of brain aging and injury are regulated by miRs. We highlight how certain miRs can mediate deregulation of genes involved in neuroinflammation, acute neuronal injury and chronic neurodegenerative diseases. Finally, we review the recent progress in the development of effective strategies to block specific miR functions and discuss future approaches with the prediction that anti-miR drugs may soon be used in the clinic.

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Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions
Zhi-Ying Tian, Chun-Yan Wang, Tao Wang, Yan-Chun Li, Zhan-You Wang
Aging and disease    2019, 10 (4): 756-769.   DOI: 10.14336/AD.2018.0912
Accepted: 20 September 2018

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Evidence has been accumulating that zinc ions can trigger β-amyloid (Aβ) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer’s disease (AD). Chelating zinc inhibits Aβ aggregation and may hold promise as a therapeutic strategy for AD. S100A6 is an acidic Ca2+/Zn2+-binding protein found only in a small number of astrocytes in the normal brain. However, in the AD brain, S100A6 is highly expressed in astrocytes around Aβ plaques. The role of the astrocytic S100A6 upregulation in AD is unknown. In the present study, we examined the effects of S100A6 on Aβ plaques and intracellular zinc levels in a mouse model of AD. Chronic exposure to zinc increased Aβ deposition and S100A6 expression, both reversible by the zinc chelator clioquinol, in the brains of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice. To examine whether exogenous S100A6 could induce Aβ plaque disaggregation through competition for zinc in vitro, we incubated APP/PS1 mouse brain sections with recombinant human S100A6 protein or co-incubated them with human S100A6-expressing cells. Both treatments efficiently reduced the Aβ plaque burden in situ. In addition, treatment with exogenous S100A6 protected cultured COS-7 cells against zinc toxicity. Our results show for the first time that increased S100A6 levels correlate with both Aβ disaggregation and decrease of Aβ plaque-associated zinc contents in brain sections with AD-like pathology. Astrocytic S100A6 in AD may protect from Aβ deposition through zinc sequestration.

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Involvement of the MiR-181b-5p/HMGB1 Pathway in Ang II-induced Phenotypic Transformation of Smooth Muscle Cells in Hypertension
Feng-Juan Li, Cheng-Long Zhang, Xiu-Ju Luo, Jun Peng, Tian-Lun Yang
Aging and disease    2019, 10 (2): 231-248.   DOI: 10.14336/AD.2018.0510
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Phenotypic transformation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. High mobility group box-1 (HMGB1) has been reported to be involved in several pathogenic processes including VSMC proliferation and migration. The present study was designed to determine the role of HMGB1 in VSMC phenotypic transformation in hypertension. First, we demonstrated that HMGB1 was elevated in a model of Ang II-induced VSMC phenotypic transformation, which showed down-regulation of contractile proteins and up-regulation of synthetic proteins. Knockdown of HMGB1 and losartan could block the phenotypic transformation. Next, we identified three potential miRNAs for upstream regulation of HMGB1 by bioinformatic analysis; only miR-181b-5p was significantly down-regulated in Ang II-treated cells. Co-treating the cells with miR-181b-5p mimics suppressed HMGB1 expression as well as the phenotypic transformation, migration, and proliferation. Furthermore, the luciferase reporter gene assay confirmed the direct interaction between miR-181b-5p and HMGB1. Finally, to extend these cell-based studies to clinical patients, we demonstrated that plasma miR-181b-5p levels were decreased, while Ang II and HMGB1 levels, as well as the intima-media thickness (IMT) were increased in hypertensive patients; these effects were reversed following the administration of angiotensin receptor blockers. Based on these observations, we conclude that the down-regulation of miR-181b-5p leads to the elevation of HMGB1 levels in hypertensive patients, which accounts, at least partially, for VSMCs phenotypic transformation and vascular remodeling. Our findings also highlight that the plasma levels of miR-181b-5p and HMGB1 may serve as novel biomarkers for vascular remodeling in the hypertensive patients.

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Traditional Oriental Medicines and Alzheimer’s Disease
Seong Gak Jeon, Eun Ji Song, Dongje Lee, Junyong Park, Yunkwon Nam, Jin-il Kim, Minho Moon
Aging and disease    2019, 10 (2): 307-328.   DOI: 10.14336/AD.2018.0328
Accepted: 29 August 2018

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Alzheimer’s disease (AD), which is the most major cause of dementia, is a progressive neurodegenerative disease that affects cognitive functions. Even though the prevalence of AD is continuously increasing, few drugs including cholinesterase inhibitors and N-methyl D-aspartate-receptor antagonists were approved to treat AD. Because the clinical trials of AD drugs with single targets, such as β-amyloid and tau, have failed, the development of multi-target drugs that ameliorate many of the symptoms of AD is needed. Thus, recent studies have investigated the effects and underlying mechanisms of herbal formulae consisting of various herb combinations used to treat AD. This review discusses the results of clinical and nonclinical studies of the therapeutic efficacy in AD and underlying mechanisms of the herbal formulae of traditional Oriental medicines and bioactive compounds of medicinal plants.

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MicroRNAs or Long Noncoding RNAs in Diagnosis and Prognosis of Coronary Artery Disease
Yuan Zhang, Lei Zhang, Yu Wang, Han Ding, Sheng Xue, Hongzhao Qi, Peifeng Li
Aging and disease    2019, 10 (2): 353-366.   DOI: 10.14336/AD.2018.0617
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Coronary artery disease (CAD) is the result of atherosclerotic plaque development in the wall of the coronary arteries. The underlying mechanism involves atherosclerosis of the arteries of the heart which is a relatively complex process comprising several steps. In CAD, atherosclerosis induces functional and structural changes. The pathogenesis of CAD results from various changes in and interactions between multiple cell types in the artery walls; these changes mainly include endothelial cell (EC) dysfunction, vascular smooth muscle cell (SMC) alteration, lipid deposition and macrophage activation. Various blood markers associated with an increased risk for cardiovascular endpoints have been identified; however, few have yet been shown to have a diagnostic impact or important clinical implications that would affect patient management. Noncoding RNAs, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), can be stable in plasma and other body fluids and could therefore serve as biomarkers for some diseases. Many studies have shown that some miRNAs and lncRNAs play key roles in heart and vascular development and in cardiac pathophysiology. Thus, we summarize here the latest research progress, focusing on the molecular mechanism of miRNAs and lncRNAs in CAD, with the intent of seeking new targets for the treatment of heart disease.

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Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours
Artur Anisiewicz, Beata Filip-Psurska, Agata Pawlik, Anna Nasulewicz-Goldeman, Tomasz Piasecki, Konrad Kowalski, Magdalena Maciejewska, Joanna Jarosz, Joanna Banach, Diana Papiernik, Andrzej Mazur, Andrzej Kutner, Jeanette A Maier, Joanna Wietrzyk
Aging and disease    2019, 10 (5): 977-991.   DOI: 10.14336/AD.2018.0921
Accepted: 28 September 2018

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Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.

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Entorhinal Cortex Atrophy in Early, Drug-naive Parkinson’s Disease with Mild Cognitive Impairment
Xiuqin Jia, Zhijiang Wang, Tao Yang, Ying Li, Shuai Gao, Guorong Wu, Tao Jiang, Peipeng Liang
Aging and disease    2019, 10 (6): 1221-1232.   DOI: 10.14336/AD.2018.1116
Accepted: 18 November 2018
Online available: 18 November 2018

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Patients with Parkinson’s disease (PD) generally have a higher proportion of suffering from mild cognitive impairment (MCI) than normal aged adults. This study aimed to identify the specific neuroanatomical alterations in early, drug-naive PD with MCI (PD-MCI) by comparing to those PD with normal cognition (PD-NC) and healthy controls (HCs), which could help to elucidate the underlying neuropathology and facilitate the development of early therapeutic strategies for treating this disease. Structural MRI data of 237 early, drug-naive non-demented PD patients (classified as 61 PD-MCI and 176 PD-NC) and 69 HCs were included from Parkinson's Progression Markers Initiative (PPMI) database after data quality control. Within these data, a subset of 61 HCs and a subset of 61 PD-NC who were matched to the 61 PD-MCI group for age, gender, and education-level were selected to further eliminate the sample size effect. The gray matter (GM) volume changes between groups were analyzed using voxel-based morphometry (VBM). Furthermore, correlations between GM volume alterations and neuropsychological performances and non-cognitive assessments (including olfactory performance) were further examined. Compared to HC, patients with PD-NC and PD-MCI commonly exhibited atrophies in the bilateral amygdala (AM) and the left primary motor cortex (M1). Patients with PD-MCI exclusively exhibited atrophy in the right entorhinal cortex (ENT) compared to PD-NC. Significantly negative correlations were found between GM loss in the bilateral AM and olfactory performance in all PD patients, and between ENT loss and memory performance in PD-MCI. The findings suggest that the right ENT atrophy may subserve as a biomarker in early, drug-naive PD-MCI, which shed light on the neural underpinnings of the disease and provide new evidence on differentiating the neuroanatomical states between PD-MCI and PD-NC.

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Galectin-3 Mediates Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension
Tangzhiming Li, Lihuang Zha, Hui Luo, Suqi Li, Lin Zhao, Jingni He, Xiaohui Li, Qiangqiang Qi, Yuwei Liu, Zaixin Yu
Aging and disease    2019, 10 (4): 731-745.   DOI: 10.14336/AD.2018.1001
Accepted: 27 November 2018

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Galectin-3 (Gal-3) is highly expressed in fibrotic tissue related to diverse etiologies. endothelial-to-mesenchymal transition (EndoMT), A less well studied phenomenon serves as a critical process in pulmonary vascular remodeling associated with the development of pulmonary arterial hypertension (PAH). EndoMT is hypothesized to contribute to the over-proliferation of αSMA positive cells. We aim to investigate the potential role of Gal-3 in regulating EndoMT in PAH. We observed an upregulation in both Gal-3 and αSMA expression in the monocrotaline (MCT) and Hypoxia PAH model, accompanied with intimal thickening. For more profound vascular remodeling and endothelial layer lesion in former model, we employed Gal-3 knockdown and overexpression lentivirus methodology to the MCT rats to determine the mechanisms underlying abnormal endothelial cell transition in PAH. PAH was evaluated according to right ventricular systolic pressure, right heart hypertrophy and pulmonary artery remodeling. A reduction in Gal-3 was protective against the development of PAH, while Gal-3 upregulation aggravated pulmonary vascular occlusion. In addition, Gal-3 deficiency suppressed pulmonary vascular cell proliferation and macrophage infiltration. Finally, we revealed that in endothelial cells treated with tumor necrosis factor α and hypoxia (representing an in vitro model of PAH), inhibition of Gal-3 by siRNA was able to abolish the associated upregulation of αSMA. These observations suggesting Gal-3 serves as a critical mediator in PAH by regulating EndoMT. Inhibition of Gal-3 may represent a novel therapeutic target for PAH treatment.

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Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging
Min-jun Wang, Jiajia Chen, Fei Chen, Qinggui Liu, Yu Sun, Chen Yan, Tao Yang, Yiwen Bao, Yi-Ping Hu
Aging and disease    2019, 10 (4): 871-882.   DOI: 10.14336/AD.2018.1119
Accepted: 26 November 2018

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Although aging is a physiological process, it has raised interest in the science of aging and rejuvenation because of the increasing burden on the rapidly aging global population. With advanced age, there is a decline in homeostatic maintenance and regenerative responsiveness to the injury of various tissues, thereby contributing to the incidence of age-related diseases. The primary cause of the functional declines that occur along with aging is considered to be the exhaustion of stem cell functions in their corresponding tissues. Age-related changes in the systemic environment, the niche, and stem cells contribute to this loss. Thus, the reversal of stem cell aging at the cellular level might lead to the rejuvenation of the animal at an organismic level and the prevention of aging, which would be critical for developing new therapies for age-related dysfunction and diseases. Here, we will explore the effects of aging on stem cells in different tissues. The focus of this discussion is on pro-youth interventions that target intrinsic stem cell properties, environmental niche component, systemic factors, and senescent cellular clearance, which are promising for developing strategies related to the reversal of aged stem cell function and optimizing tissue repair processes.

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Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease
Ashok K. Shetty, Raghavendra Upadhya, Leelavathi N. Madhu, Maheedhar Kodali
Aging and disease    2019, 10 (2): 470-482.   DOI: 10.14336/AD.2019.0330
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The mechanisms that underlie the pathophysiology of aging, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and stroke are not fully understood and have been the focus of intense and constant investigation worldwide. Studies that provide insights on aging and age-related disease mechanisms are critical for advancing novel therapies that promote successful aging and prevent or cure multiple age-related diseases. The April 2019 issue of the journal, "Aging & Disease" published a series of articles that confer fresh insights on numerous age-related conditions and diseases. The age-related topics include the detrimental effect of overweight on energy metabolism and muscle integrity, senoinflammation as the cause of neuroinflammation, the link between systemic C-reactive protein and brain white matter loss, the role of miR-34a in promoting healthy heart and brain, the potential of sirtuin 3 for reducing cardiac and pulmonary fibrosis, and the promise of statin therapy for ameliorating asymptomatic intracranial atherosclerotic stenosis. Additional aging-related articles highlighted the involvement of miR-181b-5p and high mobility group box-1 in hypertension, Yes-associated protein in cataract formation, multiple miRs and long noncoding RNAs in coronary artery disease development, the role of higher meat consumption on sleep problems, and the link between glycated hemoglobin and depression. The topics related to ALS suggested that individuals with higher education and living in a rural environment have a higher risk for developing ALS, and collagen XIX alpha 1 is a prognostic biomarker of ALS. The topics discussed on AD implied that extracellular amyloid β42 is likely the cause of intraneuronal neurofibrillary tangle accumulation in familial AD and traditional oriental concoctions may be useful for slowing down the progression of AD. The article on stroke suggested that inhibition of the complement system is likely helpful in promoting brain repair after ischemic stroke. The significance of the above findings for understanding the pathogenesis in aging, ALS, AD, and stroke, slowing down the progression of aging, ALS and AD, and promoting brain repair after stroke are discussed.

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Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease
Yu-Sheng Li, Zhi-Hua Yang, Yao Zhang, Jing Yang, Dan-Dan Shang, Shu-Yu Zhang, Jun Wu, Yan Ji, Lu Zhao, Chang-He Shi, Yu-Ming Xu
Aging and disease    2019, 10 (4): 908-914.   DOI: 10.14336/AD.2018.1109
Accepted: 23 November 2018

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Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) mutations are responsible for autosomal dominant early-onset Alzheimer’s disease (AD-EOAD). To analyze the phenotypes and genotypes of EOAD patients, we performed comprehensive clinical assessments as well as mutation screening of PSEN1, PSEN2, and exons 16 and 17 of APP by Sanger sequencing in the three Chinese EOAD families. We identified two novel mutations of PSEN1 (Y256N and H214R) in samples from these families, and a de novo mutation of PSEN1 (G206V) in a patient with very early-onset sporadic Alzheimer’s disease. A combination of bioinformatics tools based on evolutionary, structural and computational methods predicted that the mutations were all deleterious. These findings suggest that PSEN1 Y256N, H214R, and G206V need to be considered as potential causative mutations in EOAD patients. Further functional studies are needed to evaluate the roles of these mutations in the pathogenesis of AD.

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The Peptide-Directed Lysosomal Degradation of CDK5 Exerts Therapeutic Effects against Stroke
Ya-Fan Zhou, Jing Wang, Man-Fei Deng, Bin Chi, Na Wei, Jian-Guo Chen, Dan Liu, Xiaoping Yin, Youming Lu, Ling-Qiang Zhu
Aging and disease    2019, 10 (5): 1140-1145.   DOI: 10.14336/AD.2018.1225
Accepted: 31 December 2018

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The aberrant activation of CDK5 has been implicated in neuronal death in stroke. The goal of this study is to determine whether knocking down CDK5 by a peptide-directed lysosomal degradation approach is therapeutically effective against stroke. We synthesized a membrane-permeable peptide that specifically binds to CDK5 with a chaperone-mediated autophagy targeting motif (Tat-CDK5-CTM) and tested its therapeutic effects on a mouse model of ischemic stroke. Our results showed that Tat-CDK5-CTM blocked the CDK5-NR2B interaction, resulting in the degradation of CDK5, which in turn prevented calcium overload and neuronal death in cultured neurons. Tat-CDK5-CTM also reduced the infarction area and neuronal loss and improved the neurological functions in MCAO (Middle cerebral artery occlusion) mice. The peptide-directed lysosomal degradation of CDK5 is a promising therapeutic intervention for stroke.

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Reactive Astrocytes in Neurodegenerative Diseases
Kunyu Li, Jiatong Li, Jialin Zheng, Song Qin
Aging and disease    2019, 10 (3): 664-675.   DOI: 10.14336/AD.2018.0720
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Astrocytes, the largest and most numerous glial cells in the central nervous system (CNS), play a variety of important roles in regulating homeostasis, increasing synaptic plasticity and providing neuroprotection, thus helping to maintain normal brain function. At the same time, astrocytes can participate in the inflammatory response and play a key role in the progression of neurodegenerative diseases. Reactive astrocytes are strongly induced by numerous pathological conditions in the CNS. Astrocyte reactivity is initially characterized by hypertrophy of soma and processes, triggered by different molecules. Recent studies have demonstrated that neuroinflammation and ischemia can elicit two different types of reactive astrocytes, termed A1s and A2s. However, in the case of astrocyte reactivity in different neurodegenerative diseases, the recently published research issues remain a high level of conflict and controversy. So far, we still know very little about whether and how the function or reactivity of astrocytes changes in the progression of different neurodegenerative diseases. In this review, we aimed to briefly discuss recent studies highlighting the complex contribution of astrocytes in the process of various neurodegenerative diseases, which may provide us with new prospects for the development of an excellent therapeutic target for neurodegenerative diseases.

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Salsalate Prevents β-Cell Dedifferentiation in OLETF Rats with Type 2 Diabetes through Notch1 Pathway
Fei Han, Xiaochen Li, Juhong Yang, Haiyi Liu, Yi Zhang, Xiaoyun Yang, Shaohua Yang, Bai Chang, Liming Chen, Baocheng Chang
Aging and disease    2019, 10 (4): 719-730.   DOI: 10.14336/AD.2018.1221
Accepted: 30 December 2018

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A strategic approach is urgently needed to curb the growing global epidemic of diabetes. In this study, we investigated the effects and mechanisms of salsalate (SAL), an anti-inflammatory drug with anti-diabetic properties, assessing its potential to prevent diabetes in Otsuka Long-Evans Tokushima Fatty rats (OLETF). All animals in our placebo group developed diabetes, whereas none in the SAL test group did so, and only 25% of SAL-treated rats displayed impaired glucose tolerance (IGT). SAL lowered levels of glucagon and raised levels of insulin in plasma, while improving both insulin sensitivity and β-cell function. The protective effect of SAL is likely due to diminished β-cell dedifferentiation, manifested as relative declines in Neurogenin 3+/insulin- cells and synaptophysin+/islet hormone- cells and increased expression of β-cell-specific transcription factor Foxo1. Both Notch1-siRNA and N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT; an indirect inhibitor of the Notch1 pathway) were shown to prevent β-cell dedifferentiation. Similar to DAPT, SAL effectively reduced β-cell dedifferentiation, significantly suppressing Notch1 pathway activation in INS-1 cells. The inhibitory role of SAL in β-cell dedifferentiation may thus be attributable to Notch1 pathway suppression.

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Hydroxyurea Facilitates Manifestation of Disease Relevant Phenotypes in Patients-Derived IPSCs-Based Modeling of Late-Onset Parkinson’s Disease
Yuan Tan, Minjing Ke, Zhijian Huang, Cheong-Meng Chong, Xiaotong Cen, Jia-Hong Lu, Xiaoli Yao, Dajiang Qin, Huanxing Su
Aging and disease    2019, 10 (5): 1037-1048.   DOI: 10.14336/AD.2018.1216
Accepted: 08 January 2019

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Induced pluripotent stem cells (iPSCs)-derived dopaminergic neurons might be reset back to the fetal state due to reprogramming. Thus, it is a compelling challenge to reliably and efficiently induce disease phenotypes of iPSCs-derived dopaminergic neurons to model late-onset Parkinson’s disease (PD). Here, we applied a small molecule, hydroxyurea (HU), to promote the manifestation of disease relevant phenotypes in iPSCs-based modeling of PD. We established two iPS cell lines derived from two sporadic PD patients. Both patients-iPSCs-derived dopaminergic neurons did not display PD relevant phenotypes after 6 weeks culture. HU treatment remarkably induced ER stress on patients-iPSCs-derived dopaminergic neurons. Moreover, HU treatment significantly reduced neurite outgrowth, decreased the expression of p-AKT and its downstream targets (p-4EBP1 and p-ULK1), and increased the expression level of cleaved-Caspase 3 in patients-iPSCs-derived dopaminergic neurons. The findings of the present study suggest that HU administration could be a convenient and reliable approach to induce disease relevant phenotypes in PD-iPSCs-based models, facilitating to study disease mechanisms and test drug effects.

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Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease
Raquel Maeso-Díaz, Martí Ortega-Ribera, Erica Lafoz, Juan José Lozano, Anna Baiges, Rubén Francés, Agustín Albillos, Carmen Peralta, Juan Carlos García-Pagán, Jaime Bosch, Victoria C Cogger, Jordi Gracia-Sancho
Aging and disease    2019, 10 (4): 684-698.   DOI: 10.14336/AD.2019.0127
Accepted: 18 February 2019

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Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for 15 days. Hepatic and systemic hemodynamic, liver cells phenotype and hepatic fibrosis were evaluated. Additionally, the gene expression signature of cirrhosis was evaluated in a cohort of young and aged cirrhotic patients. Aged animals developed a more severe form of aCLD. Portal hypertension and liver fibrosis were exacerbated as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell-death and poorer function, LSEC were further capillarized, HSC over-activated and macrophage infiltration was significantly increased. The gene expression signature of cirrhosis significantly differed comparing young and aged patients, indicating alterations in sinusoidal-protective pathways and confirming the pre-clinical observations. Simvastatin administration for 15-day to aged cirrhotic rats improved the hepatic sinusoidal milieu, leading to significant amelioration in portal hypertension. This study provides evidence that aCLD pathobiology is different in aged individuals. As the median age of patients with aCLD is increasing, we propose a real-life pre-clinical model to develop more reliable therapeutic strategies. Simvastatin effects in this model further demonstrate its translational potential.

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The Metabolic Activity of Caudate and Prefrontal Cortex Negatively Correlates with the Severity of Idiopathic Parkinson’s Disease
Jun-Sheng Chu, Ting-Hong Liu, Kai-Liang Wang, Chun-Lei Han, Yun-Peng Liu, Shimabukuro Michitomo, Jian-Guo Zhang, Tie Fang, Fan-Gang Meng
Aging and disease    2019, 10 (4): 847-853.   DOI: 10.14336/AD.2018.0814
Accepted: 20 September 2018

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Positron emission tomography (PET) scan with tracer [18F]-fluorodeoxy-glucose (18F-FDG) is widely used to measure the glucose metabolism in neurodegenerative disease such as Idiopathic Parkinson’s disease (IPD). Previous studies using 18F-FDG PET mainly focused on the motor or non-motor symptoms but not the severity of IPD. In this study, we aimed to determine the metabolic patterns of 18F-FDG in different stages of IPD defined by Hoehn and Yahr rating scale (H-Y rating scale) and to identify regions in the brain that play critical roles in disease progression. Fifty IPD patients were included in this study. They were 29 men and 21 women (mean±SD, age 57.7±11.1 years, disease duration 4.0±3.8 years, H-Y 2.2±1.1). Twenty healthy individuals were included as normal controls. Following 18F-FDG PET scan, image analysis was performed using Statistical Parametric Mapping (SPM) and Resting-State fMRI Data Analysis Toolkit (REST). The metabolic feature of IPD and regions-of-interests (ROIs) were determined. Correlation analysis between ROIs and H-Y stage was performed. SPM analysis demonstrated a significant hypometabolic activity in bilateral putamen, caudate and anterior cingulate as well as left parietal lobe, prefrontal cortex in IPD patients. In contrast, hypermetabolism was observed in the cerebellum and vermis. There was a negative correlation (p=0.007, r=-0.412) between H-Y stage and caudate metabolic activity. Moreover, the prefrontal area also showed a negative correlation with H-Y (P=0.033, r=-0.334). Thus, the uptake of FDG in caudate and prefrontal cortex can potentially be used as a surrogate marker to evaluate the severity of IPD.

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Total Burden of Cerebral Small Vessel Disease in Recurrent ICH versus First-ever ICH
Mangmang Xu, Yajun Cheng, Quhong Song, Ruozhen Yuan, Shuting Zhang, Zilong Hao, Ming Liu
Aging and disease    2019, 10 (3): 570-577.   DOI: 10.14336/AD.2018.0804
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The relationship between recurrent intracerebral hemorrhage (ICH) and total burden of cerebral small vessel disease (CSVD) is not completely investigated. We aimed to study whether recurrent intracerebral hemorrhage (ICH) had higher CSVD score than first-ever ICH. Lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), cortical superficial siderosis (cSS) and CSVD score were rated on brain magnetic resonance imaging (MRI) in primary ICH patients. Recurrent ICHs were confirmed by reviewing the medical records and MRI scans. Mixed hematomas were defined as follows: deep + lobar, deep + cerebellar, or deep + lobar + cerebellar. Of the 184 patients with primary ICH enrolled (mean age, 61.0 years; 75.5% men), recurrent ICH was present in 45 (24.5%) patients; 26.1% (48/184) had ≥2 hematomas, 93.8% (45/48) of which exhibited recurrent ICH. Mixed hematomas were identified in 8.7% (16/184) of patients and bilateral hematomas in 17.9% (33/184). All mixed hematomas and bilateral hematomas were from cases of recurrent ICH. Patients with mixed etiology-ICH were more likely to have recurrent ICH than patients with cerebral amyloid angiopathy (CAA) or hypertensive angiopathy (HA)-related ICH (36.8% vs17.8%, p=0.008). Multivariate ordinal regression analysis showed that the presence of recurrent ICH (p=0.001), ≥2 hematomas (p=0.002), mixed hematomas (p<0.00001), and bilateral hematomas (p=0.002) were separately significantly associated with a high CSVD score. Recurrent ICH occurs mostly among patients with mixed etiology-ICH and is associated with a higher CSVD burden than first-ever ICH, which needs to be verified by future larger studies.

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Prospective Study of Glycated Hemoglobin and Trajectories of Depressive Symptoms: The China Health and Retirement Longitudinal Study
Haibin Li, Anxin Wang, Wei Feng, Deqiang Zheng, Qi Gao, Lixin Tao, Jin Guo, Xiaonan Wang, Xia Li, Wei Wang, Xiuhua Guo
Aging and disease    2019, 10 (2): 249-257.   DOI: 10.14336/AD.2018.0410
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The longitudinal association between glycated hemoglobin (HbA1c) and different courses of depressive symptoms is understudied. This study aimed to identify different trajectories of depressive symptoms and investigate the relation of HbA1c with the risk of increasing and high-stable depressive symptoms. In the China Health and Retirement Longitudinal Study, depressive symptoms were measured using the 10-item Center for Epidemiological Studies-Depression scale in three visits (years: 2011, 2013 and 2015) among 9804 participants (mean age 60.0 ± 9.0 years). Group-based trajectory modeling was used to identify trajectories of depressive symptoms. HbA1c was measured at baseline and categorized five groups according to the respective quintile. Multinomial logistic regression was fitted to examine this relationship. Four distinct trajectories of depressive symptoms were identified: low symptoms (n=6401, 65.29%); decreasing symptoms (n=1362, 13.89%); increasing symptoms (n=1452, 14.81%); and high symptoms (n=1452, 14.81%). Adjusting for demographic, health-related, and cognitive factors, the risk ratio (95% confidence interval) pertaining to the highest HbA1c (Quintile 5) for decreasing, increasing, and high symptoms of depression versus low symptoms was 1.01 (0.82-1.25), 1.12 (0.92-1.36), and 1.39 (1.04-1.86) compared with the lowest HbA1c (Quintile 1), respectively. We observed a J-shaped relationship between HbA1c and high depressive symptoms, with the lowest risk at a HbA1c concentration of 5.0%. In summary, in this large population-based cohort, high levels of glycated hemoglobin concentrations were associated with a higher risk of increasing and high-stable symptoms of depression.

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Intravenous Administration of Standard Dose Tirofiban after Mechanical Arterial Recanalization is Safe and Relatively Effective in Acute Ischemic Stroke
Zhe Cheng, Xiaokun Geng, Jie Gao, Mohammed Hussain, Seong-Jin Moon, Huishan Du, Yuchuan Ding
Aging and disease    2019, 10 (5): 1049-1057.   DOI: 10.14336/AD.2018.0922
Accepted: 26 September 2018

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To investigate the safety and efficacy of intravenous administration of a standard dose of glycoprotein-IIb/IIIa inhibitor tirofiban after vessel recanalization by mechanical thrombectomy in acute ischemic stroke. A consecutive series of patients (n=112) undergoing endovascular ischemic stroke intervention therapy were enrolled. 81 patients were eligible for intravenous (IV) tirofiban treatment for 24 hours after mechanical thrombectomy. The incidence of symptomatic intracranial hemorrhage (sICH), death, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) were assessed. In the 81 patients receiving tirofiban, 52 patients (64.2%) were treated with IV rt-PA before mechanical thrombectomy. sICH was found in 2 (2.5%) patients with no fatal ICH. Four patients died during 3 months after stroke onset. Successful recanalization with thrombolysis in cerebral infarction (TICI) score ≥2b was achieved in 75 of 81 patients (92.6%) after mechanical thrombectomy. The average number of passes with Solitaire stent retriever was 1.3. At 3 months, 55 of 81 patients (67.9%) had favorable outcomes (mRS<=2). The intravenous application of a standard dose of tirofiban post-Solitaire stent retriever thrombectomy and intravenous thrombolysis appears to be safe and relatively effective in acute ischemic stroke.

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Influence of Environment and Lifestyle on Incidence and Progress of Amyotrophic Lateral Sclerosis in A German ALS Population
Sonja Korner, Johanna Kammeyer, Antonia Zapf, Magdalena Kuzma-Kozakiewicz, Maria Piotrkiewicz, Bożenna Kuraszkiewicz, Hanna Goszczynska, Marta Gromicho, Julian Grosskreutz, Peter M. Andersen, Mamede de Carvalho, Susanne Petri
Aging and disease    2019, 10 (2): 205-216.   DOI: 10.14336/AD.2018.0327
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly affecting upper and lower motor neurons in the brain and spinal cord. Pathogenesis of ALS is still unclear, and a multifactorial etiology is presumed. The remarkable clinical heterogeneity between different phenotypes of ALS patients suggests that environmental and lifestyle factors could play a role in onset and progression of ALS. We analyzed a cohort of 117 ALS patients and 93 controls. ALS patients and controls were compared regarding physical activity, dietary habits, smoking, residential environment, potentially toxic environmental factors and profession before symptom onset and throughout the disease course. Data were collected by a personal interview. For statistical analysis descriptive statistics, statistical tests and analysis of variance were used. ALS patients and controls did not differ regarding smoking, diet and extent of physical training. No higher frequency of toxic influences could be detected in the ALS group. ALS patients lived in rural environment considerably more often than the control persons, but this was not associated with a higher percentage of occupation in agriculture. There was also a higher percentage of university graduates in the ALS group. Patients with bulbar onset were considerably more often born in an urban environment as compared to spinal onset. Apart from education and environment, ALS phenotypes did not differ in any investigated environmental or life-style factor. The rate of disease progression was not influenced by any of the investigated environmental and life-style factors. The present study could not identify any dietary habit, smoking, physical activity, occupational factor as well as toxic influences as risk factor or protective factor for onset or progression of ALS. Living in rural environment and higher education might be associated with higher incidence of ALS.

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Mitochondrial Creatine Kinase is Decreased in the Serum of Idiopathic Parkinson’s Disease Patients
Jinghui Xu, Xiaodi Fu, Mengqiu Pan, Xiao Zhou, Zhaoyu Chen, Dongmei Wang, Xiaomei Zhang, Qiong Chen, Yanhui Li, Xiaoxian Huang, Guanghui Liu, Jianjun Lu, Yan Liu, Yafang Hu, Suyue Pan, Qing Wang, Qun Wang, Yunqi Xu
Aging and disease    2019, 10 (3): 601-610.   DOI: 10.14336/AD.2018.0615
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Mitochondrial creatine kinase (MtCK) is vital in the process of mitochondrial energy metabolism, and mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD). Therefore, we speculated that MtCK activity could be altered in the serum of PD patients. However, no studies to date have investigated this specific topic, so we sought to investigate the serum MtCK activities among a cohort of PD patients. 50 patients with PD and 30 age-matched controls were recruited for this study. Serum ubiquitous MtCK (uMtCK) and sarcomeric MtCK (sMtCK) activities were assayed using an immunoinhibition method. Correlations between serum uMtCK/sMtCK activities and clinical features/parameters were explored in the PD group. Our study revealed a significant decrease in the uMtCK activity in the PD group when compared with the control group. No significant difference was found in the serum sMtCK activity between the PD and control groups. There was a significant correlation between serum uMtCK activities and the disease progression rate, duration, and age at onset in PD patients. While no significant relationship was found between the serum uMtCK activities and the Hoehn & Yahr stage or main non-motor symptoms scale. There was a significant decrease in the uMtCK activity in the serum of PD patients, which was associated with the rate of disease progression, duration, and age at onset of disease. Therefore, uMtCK activity in serum offers a useful clue for identification of PD biomarkers.

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Physical Activity and Alzheimer’s Disease: A Narrative Review
Piotr Gronek, Stefan Balko, Joanna Gronek, Adam Zajac, Adam Maszczyk, Roman Celka, Agnieszka Doberska, Wojciech Czarny, Robert Podstawski, Cain C. T Clark, Fang Yu
Aging and disease    2019, 10 (6): 1282-1292.   DOI: 10.14336/AD.2019.0226
Accepted: 12 March 2019

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Although age is a dominant risk factor for Alzheimer’s disease (AD), epidemiological studies have shown that physical activity may significantly decrease age-related risks for AD, and indeed mitigate the impact in existing diagnosis. The aim of this study was to perform a narrative review on the preventative, and mitigating, effects of physical activity on AD onset, including genetic factors, mechanism of action and physical activity typology. In this article, we conducted a narrative review of the influence physical activity and exercise have on AD, utilising key terms related to AD, physical activity, mechanism and prevention, searching the online databases; Web of Science, PubMed and Google Scholar, and, subsequently, discuss possible mechanisms of this action. On the basis of this review, it is evident that physical activity and exercise may be incorporated in AD, notwithstanding, a greater number of high-quality randomised controlled trials are needed, moreover, physical activity typology must be acutely considered, primarily due to a dearth of research on the efficacy of physical activity types other than aerobic.

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Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice
Peng Yu, Poornima Venkat, Michael Chopp, Alex Zacharek, Yi Shen, Linlin Liang, Julie Landschoot-Ward, Zhongwu Liu, Rongcai Jiang, Jieli Chen
Aging and disease    2019, 10 (4): 770-783.   DOI: 10.14336/AD.2018.0816
Accepted: 27 August 2018
Online available: 26 August 2018

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Tissue plasminogen activator (tPA) is a serine protease primarily involved in mediating thrombus breakdown and regulating catabolism of amyloid-beta (Aβ). The aim of this study is to investigate age-dependent decline of endogenous tPA and the effects of tPA decline on glymphatic function and cognitive outcome in mice. Male, young (3m), adult (6m) and middle-aged (12m) C57/BL6 (wild type) and tPA knockout (tPA-/-) mice were subject to a battery of cognitive tests and white matter (WM) integrity, neuroinflammation, and glymphatic function were evaluated. Adult WT mice exhibit significantly decreased brain tPA level compared to young WT mice and middle-aged WT mice have significantly lower brain tPA levels than young and adult WT mice. Middle-aged WT mice exhibit significant neuroinflammation, reduced WM integrity and increased thrombin deposition compared to young and adult mice, and increased blood brain barrier (BBB) permeability and reduced cognitive ability compared to young WT mice. In comparison to adult WT mice, adult tPA-/- mice exhibit significant BBB leakage, decreased dendritic spine density, increased thrombin deposition, neuroinflammation, and impaired functioning of the glymphatic system. Compared to age-matched WT mice, adult and middle-aged tPA-/- mice exhibit significantly increased D-Dimer expression and decreased perivascular Aquaporin-4 expression. Compared to age-matched WT mice, young, adult and middle-aged tPA-/- mice exhibit significant cognitive impairment, axonal damage, and increased deposition of amyloid precursor protein (APP), Aβ, and fibrin. Endogenous tPA may play an important role in contributing to aging induced cognitive decline, axonal/WM damage, BBB disruption and glymphatic dysfunction in the brain.

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